It is proposed to complete the applicant's research on phenothiazine drugs and structurally related tricyclic major neuroleptics started 20 years ago within this final project period ending in August 1978 (her retirement date). The third and final support year under MH25645-03 (Chlorpromazine Excretion: Isotope vs. Chemical Assay) will provide most of the proposed data for chlorpromazine metabolism, including suitable assay procedures, for the biotransformation products of this drug in man. Current GC/MS automated procedures will be improved and simplified, and a number of major metabolites, especially in blood and urine, considered adequate to recognize inter-patient differences in drug metabolism will be used for tentative correlation with clinical response. The preparation of at least one chlorpromazine O-glucuronide of suitable purity to serve as a reference compound will also be attempted. Analogous assays for the other two classes of clinically used phenothiazines, i.e. the piperidine-linked phenothiazine (prototype: thioridazine) and the piperazine-linked phenothiazines (prototypes: prochlorperazine and fluphenazine) have been found feasible and will not present the difficulties encountered in chlorpromazine metabolism. Fewer urinary metabolities are formed and higher plasma and whole blood concentrations are seen in these phenothiazines. In some instances, high pressure liquid chromatography will be the method of choice for these drugs which can be quantitated by direct fluorescence detection as well as by variable wavelength UV detection of the drugs and their individual metabolites. If successful, the sensitive new methods would be helpful not only for establishing a long-sought ccrrelation of biochemical data with clinical parameters, but would also permit the monitoring of pertinent blood-drug concentrations, useful to clinicians in adjusting drug dosages to the therapeutic range, thus avoiding inadequate or excessive dosage.